Summary. Sub-Project 3 (Epidemiology: genes, modifiable risk factors, and risk prediction for breast cancer) will extend existing genome-wide association studies (GWAS) as well as the additional discovery efforts in Sub-Project 1 of this application by characterizing the relationships among newly-discovered common breast cancer risk alleles, known breast cancer risk factors, and breast cancer incidence. This Sub-Project will accelerate the translation of GWAS findings to clinical and public health practice by suggesting particular biologic mechanisms for breast cancer etiology (Aims 1-3) and by evaluating the clinical validity and utility of genetic risk prediction models in a variety of settings (Aims 4-6). The Sub-Project encompasses six specific aims: 1) Conduct a GWAS for new loci that interact with other, known breast cancer alleles; 2) assess gene-gene interactions among known breast cancer risk alleles; 3) assess gene-environment interactions between known breast cancer risk alleles and established risk factors, most notably modifiable exposures such as postmenopausal hormone therapy; 4) construct and compare the clinical validity of risk prediction algorithms that combine information on multiple breast cancer alleles and known risk factors; 5) evaluate the performance of these algorithms in high-risk families; and 6) assess genetic modification of prophylactic tamoxifen treatment.